Insomnia and other sleep problems are among the most common complaints dealt with by physicians, such as primary care physicians and psychiatrists. It is estimated that about 33% of the general population and up to 50% of older adults suffer from insomnia and other sleep-related disorders. Insomnia is generally defined and categorized into four categories: 1) trouble falling asleep (sleep onset—difficulty falling asleep—DFA); 2) trouble staying asleep (sleep maintenance—middle insomnia—MI); 3) waking up too early (early morning awakening—EMA); and 4) poor quality sleep (nonrestorative sleep).
There are various recognized problems with the state of the art in methods for treating insomnia. With the current state of the art, a current state of the art medication needs to be taken each time there is insomnia and each time the current state of the art medication is taken there are risks of side effects. The present state of the art for the treatment of insomnia includes medication and non-medication approaches. The present state of the art for the treatment of insomnia includes the following categories of medications and other treatments as 1.5 million Americans use complementary and alternative therapies to treat insomnia: 1) Benzodiazepine (short acting medications): Ativan (lorazepam), Xanax (alprazolam), Librium (chlordiazepoxide), Halcion (triazolam), Restoril (temazepam), Serax (oxazepam), Prosom (estazolam); 2) Benzodiazepine and Sedative hypnotics (long acting medications): Valium (diazepam), Dalmane (flurazepam), Klonopin (clonazepam), chloral hydrate, Doral (quazepam); 3) Non-benzodiazepine hypnotics: Sonata (zaleplon), Ambien (zolpidem), Rozerem (ramelteon), Lunesta (eszopiclone); 4) Antihistamine: Atarax (hydroxyzine HCL), Vistaril (hydroxyzine pamoate), Benadryl (diphenhydramine), Unisom (doxylamine); 5) Melatonin activating agents: Rozerem (ramelteon); 6) Barbiturates: Phenobarbital, Seconal (secobarbital), Tuinal; 7) Natural substances and over the counter (OTC) preparations: Tryptophan, Melatonin, valerian root, kava, tryptophan and 5-L-5-hydroxytryptophan, chamomile tea, lip balm; 8) Anti-depressants: Doxepin, trazodone, amitriptyline, mirtazapine; 9) Antipsychotics: Seroquel, Zyprexa; and 10) Orexin Inhibitors: Belsomra (suvorexant).
Some of the problems with the state-of-the-art include the following non-comprehensive list of side effects from the existing medication: 1) Benzodiazepine: confusion, addiction, paradoxical reaction, drug/drug interactions, abuse, over sedation, drug/food interactions, diversion; 2) Benzodiazepine and Sedative hypnotics: confusion, addiction, diversion, paradoxical reaction, drug/drug interactions, abuse, over sedation, drug/food interactions; 3) Non-benzodiazepine hypnotics: confusion, addiction, diversion, paradoxical reaction, drug/drug interactions, abuse, over sedation, drug/food interactions; 4) Antihistamine: confusion, paradoxical reaction, drug/drug interactions, abuse, over sedation, drug/food interactions; 5) Melatonin activating agents: lack of response, confusion, paradoxical reaction, drug/drug interactions, abuse, over sedation, drug/food interactions, dry mouth; 6) Barbiturates: confusion, addiction, paradoxical reaction, drug/drug interactions, abuse, over sedation, drug/food interactions; 7) Tryptophan: confusion, addiction, paradoxical reaction, drug/drug interactions, abuse, over sedation, drug/food interactions; 8) Anti-depressants including doxepin, trazodone, amitriptyline, mirtazapine: confusion, paradoxical reaction, manic reactions, priapism, anticholinergic delirium, drug/drug interactions, abuse, over sedation, drug/food interactions; 9) Antipsychotics including Seroquel: confusion, paradoxical reaction, drug/drug interactions, abuse, over sedation, drug/food interactions, weight gain, Diabetes Mellitus, Hyperlipidemia.
For adults over 60 years of age, studies show that the risks of prescribed sedative hypnotics far outweigh the benefits. A general recommendation is to only use sedative hypnotics 2 to 4 days per week. Dependence (a phenomenon akin to addiction), tolerance (needing more and more of a substance), and rebound insomnia (difficulty sleeping after medication is discontinued) are problems with sedative hypnotics. As a result, Consumer Reports noted for example that “chronic insomnia is undertreated and less than half of the people who need help actually get it.” Perhaps this is because there are class effect warnings associated with the available medication treatments. These class effect warnings are a problem to both doctors prescribing the medication and patients taking the medication. Some of these warning include: 1) the medications are abusable medication; 2) the medications are addicting medication; 3) the medications are controlled drugs; 4) the medications are dangerous to mix with alcohol and other agents that affect the central nervous system; 5) the medications can cause sleep walking, sleep driving, sleep telephone calling; 6) the medications can cause memory loss; 7) the medications can cause central nervous system (CNS) issues; and 8) the medications have a driving warning.
As an example of the concern the authorities have about these types of medication, the following are excerpted from the FDA authorized package insert for Belsomra (suvorexant), a medication the FDA recently approved in 2014 for the treatment of insomnia:
2 Dosage and Administration
2.1 Dosing Information
Use the lowest dose effective for the patient. The recommended dose for BELSOMRA is 10 mg, taken no more than once per night and within 30 minutes of going to bed, with at least 7 hours remaining before the planned time of awakening. If the 10 mg dose is well-tolerated but not effective, the dose can be increased. The maximum recommended dose of BELSOMRA is 20 mg once daily.
2.2 Special Populations
Exposure to BELSOMRA is increased in obese compared to non-obese patients, and in women compared to men. Particularly in obese women, the increased risk of exposure-related adverse effects should be considered before increasing the dose [see Clinical Pharmacology (12.3)].
2.3 Use with CNS Depressants
When BELSOMRA is combined with other CNS depressant drugs, dosage adjustment of BELSOMRA and/or the other drug(s) may be necessary because of potentially additive effects [see Warnings and Precautions (5.1)].
2.4 Use with CYP3A Inhibitors
The recommended dose of BELSOMRA is 5 mg when used with moderate CYP3A inhibitors and the dose generally should not exceed 10 mg in these patients. BELSOMRA is not recommended for use with strong CYP3A inhibitors [see Drug Interactions (7.2)].
2.5 Food Effect
Time to effect of BELSOMRA may be delayed if taken with or soon after a meal.
5.1 CNS Depressant Effects and Daytime Impairment
BELSOMRA is a central nervous system (CNS) depressant that can impair daytime wakefulness even when used as prescribed. Prescribers should monitor for somnolence and CNS depressant effects, but impairment can occur in the absence of symptoms, and may not be reliably detected by ordinary clinical exam (i.e., less than formal testing of daytime wakefulness and/or psychomotor performance). CNS depressant effects may persist in some patients for up to several days after discontinuing BELSOMRA.
BELSOMRA can impair driving skills and may increase the risk of falling asleep while driving. Discontinue or decrease the dose in patients who drive if daytime somnolence develops. In a study of healthy adults, driving ability was impaired in some individuals taking 20 mg BELSOMRA [see Clinical Studies (14.2)].
Although pharmacodynamic tolerance or adaptation to some adverse depressant effects of BELSOMRA may develop with daily use, patients using the 20 mg dose of BELSOMRA should be cautioned against next-day driving and other activities requiring full mental alertness. Patients taking lower doses of BELSOMRA should also be cautioned about the potential for driving impairment because there is individual variation in sensitivity to BELSOMRA.
Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Patients should be advised not to consume alcohol in combination with BELSOMRA because of additive effects [see Drug Interactions (7.1)]. Dosage adjustments of BELSOMRA and of concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of BELSOMRA with other drugs to treat insomnia is not recommended [see Dosage and Administration (2.3)].
The risk of next-day impairment, including impaired driving, is increased if BELSOMRA is taken with less than a full night of sleep remaining, if a higher than the recommended dose is taken, if co-administered with other CNS depressants, or if co-administered with other drugs that increase blood levels of BELSOMRA. Patients should be cautioned against driving and other activities requiring complete mental alertness if BELSOMRA is taken in these circumstances.
5.2 Need to Evaluate for Co-Morbid Diagnoses
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new cognitive or behavioral abnormalities may be the result of an unrecognized underlying psychiatric or physical disorder, and can emerge during the course of treatment with hypnotic drugs such as BELSOMRA.
5.3 Abnormal Thinking and Behavioral Changes
A variety of cognitive and behavioral changes (e.g., amnesia, anxiety, hallucinations and other neuro-psychiatric symptoms) have been reported to occur in association with the use of hypnotics such as BELSOMRA. Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after taking a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with the use of hypnotics. These events can occur in hypnotic-naïve as well as in hypnotic-experienced persons. The use of alcohol and other CNS depressants may increase the risk of such behaviors. Discontinuation of BELSOMRA should be strongly considered for patients who report any complex sleep behavior.
5.4 Worsening of Depression/Suicidal Ideation
In clinical studies, a dose-dependent increase in suicidal ideation was observed in patients taking BELSOMRA as assessed by questionnaire. Immediately evaluate patients with suicidal ideation or any new behavioral sign or symptom.
In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides) have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time. The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
5.5 Patients with Compromised Respiratory Function
Effect of BELSOMRA on respiratory function should be considered if prescribed to patients with compromised respiratory function. BELSOMRA has not been studied in patients with severe obstructive sleep apnea (OSA) or severe chronic obstructive pulmonary disease (COPD) [see Use in Specific Populations (8.6)].
5.6 Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, Cataplexy-like Symptoms Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions by the patient, can occur with the use of BELSOMRA. Prescribers should explain the nature of these events to patients when prescribing BELSOMRA. Symptoms similar to mild cataplexy can occur, with risk increasing with the dose of BELSOMRA. Such symptoms can include periods of leg weakness lasting from seconds to a few minutes, can occur both at night and during the day, and may not be associated with an identified triggering event (e.g., laughter or surprise).
7 Drug Interactions
7.1 CNS-Active Agents
When BELSOMRA was co-administered with alcohol, additive psychomotor impairment was demonstrated. There was no alteration in the pharmacokinetics of BELSOMRA [see Warnings and Precautions (5.1, 5.3) and Clinical Pharmacology (12.3)].
7.2 Effects of Other Drugs on BELSOMRA
Metabolism by CYP3A is the major elimination pathway for suvorexant. CYP3A Inhibitors Concomitant use of BELSOMRA with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan) is not recommended [see Clinical Pharmacology (12.3)].
The recommended dose of BELSOMRA is 5 mg in subjects receiving moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil). The dose can be increased to 10 mg in these patients if necessary for efficacy [see Clinical Pharmacology (12.3)].
CYP3A Inducers
Suvorexant exposure can be substantially decreased when co-administered with strong CYP3A inducers (e.g., rifampin, carbamazepine and phenytoin). The efficacy of BELSOMRA may be reduced [see Clinical Pharmacology (12.3)].
7.3 Effects of BELSOMRA on Other Drugs
Digoxin
Concomitant administration of BELSOMRA with digoxin slightly increased digoxin levels due to inhibition of intestinal P-gp. Digoxin concentrations should be monitored when co-administering BELSOMRA with digoxin [see Clinical Pharmacology (12.3)].
8.6 Patients with Compromised Respiratory Function
Effects of BELSOMRA on respiratory function should be considered if prescribed to patients with compromised respiratory function.
Obstructive Sleep Apnea
The respiratory depressant effect of BELSOMRA was evaluated after one night and after four consecutive nights of treatment in a randomized, placebo-controlled, 2-period crossover study in patients (n=26) with mild to moderate obstructive sleep apnea. Following once-daily doses of 40 mg, the mean 8 Apnea/Hypopnea Index treatment difference (suvorexant—placebo) on Day 4 was 2.7 (90% CI: 0.22 to 5.09), but there was wide inter- and intra-individual variability such that clinically meaningful respiratory effects of BELSOMRA in obstructive sleep apnea cannot be excluded. BELSOMRA has not been studied in patients with severe obstructive sleep apnea [see Warnings and Precautions (5.5)].
Chronic Obstructive Pulmonary Disease
The respiratory depressant effect of BELSOMRA was evaluated after one night and after four consecutive nights of treatment in a randomized, placebo-controlled, 2-period crossover study in patients (n=25) with mild to moderate chronic obstructive pulmonary disease (COPD). BELSOMRA (40 mg in non-elderly, 30 mg in elderly) had no respiratory depressant effects in patients with mild to moderate COPD, as measured by oxygen saturation. There was wide inter- and intra-individual variability such that clinically meaningful respiratory effects of BELSOMRA in COPD cannot be excluded. BELSOMRA has not been studied in patients with severe COPD [see Warnings and Precautions (5.5)].
8.7 Patients with Hepatic Impairment
No dose adjustment is required in patients with mild and moderate hepatic impairment. BELSOMRA has not been studied in patients with severe hepatic impairment and is not recommended for these patients [see Clinical Pharmacology (12.3)].
9 Drug Abuse and Dependence
9.1 Controlled Substance
BELSOMRA contains suvorexant, a Schedule IV controlled substance. 9.2 Abuse
Abuse of BELSOMRA poses an increased risk of somnolence, daytime sleepiness, decreased reaction time and impaired driving skills [see Warnings and Precautions (5.1)]. Patients at risk for abuse may include those with prolonged use of BELSOMRA, those with a history of drug abuse, and those who use BELSOMRA in combination with alcohol or other abused drugs. Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may develop after repeated abuse of a prescription or over-the-counter drug, including: a strong desire to take the drug, difficulties in controlling drug use, persisting in drug use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, as well as the possibility of the development of tolerance or development of physical dependence (as manifest by a withdrawal syndrome). Drug abuse and drug addiction are separate and distinct from physical dependence and tolerance (for example, abuse or addiction are not always accompanied by tolerance or physical dependence). In an abuse liability study conducted in recreational polydrug users (n=36), suvorexant (40, 80 and 150 mg) produced similar effects as zolpidem (15, 30 mg) on subjective ratings of “drug liking” and other measures of subjective drug effects. Because individuals with a history of abuse or addiction to alcohol or other drugs may be at increased risk for abuse and addiction to BELSOMRA, follow such patients carefully.
9.3 Dependence
Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. In completed clinical trials with BELSOMRA, there was no evidence for physical dependence with the prolonged use of BELSOMRA.
There were no reported withdrawal symptoms after discontinuation of BELSOMRA.
The following warnings are of particular concern: “Do not drive, operate heavy machinery, do other dangerous activities, or do other activities that require clear thinking after taking BELSOMRA,” and “Do not take unless you are able to stay in bed a full night (at least 7 hours) before you must be active again.”
In addition to the fact that all of the above medications (categories 1-10), whether indicated for sleep or a variety of other biological conditions, have their own significant list of side effects and risks, there is a lack of specificity attached to these medications. This means that all of these medications, whether indicated for sleep or for a variety of other biological conditions, only work on an unpredictable percentage or segment of the population. Alternative medication teaches us that there is a whole category of approaches that have less side effects. Holistic approaches to improve sleep include relaxation techniques, cognitive behavioral therapy for sleep, counting sheep, using the bedroom only for sleep, listening to music, watching television, exercise, hypnosis, and/or hard work before sleep, etc. While these approaches have very limited side effects, they also have very limited benefits and those benefits are only effective for a very limited percentage of the population as well. Although all of the medications and procedures noted above are known to benefit a certain percentage of the population, that percentage of the population is never well-defined by a biological procedure or technique and only discovered by trial and error.
Phosphodiesterase type 5 (PDE5) is an enzyme from the phosphodiesterase class found in various tissues such as the corpus cavernosum, the lung, and the retina, and which also play a role in the cardiovascular system. The 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) comprise a large class of enzymes divided into at least eleven different families which are structurally, biochemically and pharmacologically distinct from one another. The enzymes within each family are commonly referred to as isoenzymes, or isozymes. Further diversity among the isoenzymes results from differential splicing and post-translational processing of those gene products. PDE5 is characterized by selective, high affinity hydrolytic degradation of the second messenger cyclic nucleotide, guanosine 3′,5′-cyclic monophosphate (cGMP).
The Latin term impotentia coeundi describes the simple inability to insert the penis into the vagina. The term is now mostly replaced by more precise terms, such as erectile dysfunction (ED). The study of erectile dysfunction within medicine is covered by andrology, a sub-field within urology. Research indicates that erectile dysfunction is common, and it is suggested that approximately 40% of males suffer from erectile dysfunction or impotence, at least occasionally (Schouten et al., 2010, J. Sex. Med. 7(7):2547-2553). Erectile dysfunction, defined as an inability to achieve an erection that is capable of helping a male engage in sexual intercourse, is a specific problem, primarily beginning in men 40 years of age or older, increasing in frequency with age, affecting a significant number of men as they age. Erectile dysfunction (ED), or impotence, is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual activity. A penile erection is the hydraulic effect of blood entering and being retained in sponge-like bodies within the penis. The process is most often initiated as a result of sexual arousal, when signals are transmitted from the brain to nerves in the penis. The most important organic causes of ED are cardiovascular disease and diabetes, neurological problems (for example, trauma from prostatectomy surgery), hormonal insufficiencies (hypogonadism) and drug side effects. Psychological impotence is where erection or penetration fails due to thoughts or feelings (psychological reasons) rather than physical causes. Erectile dysfunction can have severe psychological consequences as it can be tied to relationship difficulties and masculine self-image. Besides treating the underlying causes such as potassium deficiency or arsenic contamination of drinking water, the first line treatment of erectile dysfunction most often consists of a trial of PDE5 inhibitors (Montague et al., 2005, J. Urol. 174(1):230-239).
PDE5 inhibitors were first targeted to treat pulmonary hypertension and then marketed to treat erectile dysfunction (ED). Phosphodiesterase 5 inhibitors, including, but not limited to, avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, zaprinast, icariin and benzamidenafil. Sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra, Staxyn) and Stendra (avanafil) are specifically indicated for erectile dysfunction in males, only. A whole series of PDE5 inhibiting substances are known from the prior art and are described as potent and effective substances for the treatment of erectile dysfunction. By inducing relaxation of the vasculature within the corpus cavernosum of the penis, they increase the blood flow, thereby inducing tumescence of the penis. Relaxation of the vasculature is initiated by the release of NO from adrenergic neurons which subsequently activates the guanylyl cyclase of smooth muscle cells of the vessels of the corpus cavernosum. Once activated guanylyl cyclase synthesizes the second messenger cGMP which mediates the relaxation of the cell. PDE5 inhibitors prevent the degradation of cGMP by phosphodiesterase 5, thereby prolonging and enhancing the effects of cGMP. It has been demonstrated in several animal models and recently in several clinical trials that PDE5 inhibitors reduce the symptoms of pulmonary hypertension and commencing right-heart failure (Michelakis et al., 2003, Circulation 108: 2066; Ghofrani et al., 2003, J. Am. Coll. Cardiol. 42: 158; Ghofrani et al., 2002, Lancet 360: 895; Ghofrani et al., 2003, AJRCCM 167(8):1139). Furthermore, despite the fact that the mode of action is not clear, it has been shown that the PDE5 inhibitor sildenafil (Viagra, RTM) induces neurogenesis and promotes functional recovery after stroke in rats (Zhang et al., 2002, Stroke 33:2675-2680; Zhang et al., 2003, Circ. Res. 92(3):308). In a dog model of congestive heart failure it has been shown that chronic administration of a phosphodiesterase type 5 inhibitor suppresses renal production of endothelin-1 (Yamamoto et al., 2002, Clin. Sci. (Lond.) 103:258S). In addition sildenafil has been shown to relax epicardial coronary arteries of patients with coronary artery disease (Halcox et al., 2002, J. Am. Coll. Cardiol., 40:1232) and some animal studies suggest that sildenafil might work in diabetic gastropathy (Bianco et al., 2002, Diabetes Care, 25:1888) in which nNOS expression and activity seems to be reduced (Watkins et al., 2000, J. Clin. Invest., 106:373).
There is a need in the art for novel methods of treating insomnia, in particular methods which avoid manipulating the central nervous system, and with less chances of minor and major side effects, and less chance of abuse or addiction. This invention fulfills this need.